U.S. patent application number 09/846003 was filed with the patent office on 2001-12-27 for process for preparing piperidines.
Invention is credited to Diehl, Herbert, Frohn, Lutz, Giffels, Guido, Hammerschmidt, Erich, Martin, Georg.
Application Number | 20010056186 09/846003 |
Document ID | / |
Family ID | 7641189 |
Filed Date | 2001-12-27 |
United States Patent
Application |
20010056186 |
Kind Code |
A1 |
Giffels, Guido ; et
al. |
December 27, 2001 |
Process for preparing piperidines
Abstract
Piperidines are prepared in an advantageous manner by catalytic
hydrogenation of activated pyridines in the presence of palladium
catalysts if the palladium catalyst is palladium-on-carbon and the
solvents are aromatic hydrocarbons.
Inventors: |
Giffels, Guido; (Bonn,
DE) ; Diehl, Herbert; (Leverkusen, DE) ;
Martin, Georg; (Langenfeld, DE) ; Frohn, Lutz;
(Erkrath, DE) ; Hammerschmidt, Erich; (Bergisch
Gladbach, DE) |
Correspondence
Address: |
BAYER CORPORATION
PATENT DEPARTMENT
100 BAYER ROAD
PITTSBURGH
PA
15205
US
|
Family ID: |
7641189 |
Appl. No.: |
09/846003 |
Filed: |
April 30, 2001 |
Current U.S.
Class: |
546/245 ;
546/113; 546/225 |
Current CPC
Class: |
C07D 211/02 20130101;
C07D 471/04 20130101; C07D 211/60 20130101 |
Class at
Publication: |
546/245 ;
546/225; 546/113 |
International
Class: |
C07D 211/36; C07D
211/32 |
Foreign Application Data
Date |
Code |
Application Number |
May 8, 2000 |
DE |
10022369.9 |
Claims
What is claimed is:
1. A process for preparing piperidines comprising catalytically
hydrogenating activated pyridines in the presence of a palladium
catalyst and an aromatic hydrocarbon solvent, wherein the palladium
catalyst is palladium-on-carbon.
2. A process according to claim I wherein the activated pyridines
have the formula (I) 3wherein R.sup.1 represents COOR.sup.3,
CONH.sub.2, CO--NH--COR.sup.3, or COOH groups or two adjacent
R.sup.1 groups together represent a CO--NR.sup.4-CO group, R.sup.2
represents linear or branched C.sub.1-C.sub.20-alkyl or halogen,
R.sup.3 represents linear or branched C.sub.1-C.sub.6-alkyl,
phenyl, or benzyl, R.sup.4 represents hydrogen, linear or branched
C.sub.1-C.sub.6-alkyl, phenyl, or benzyl, n represents 1 or 2, and
m represents zero, 1, or 2, and the resultant piperidines have the
formula (II) 4wherein R.sup.1, R.sup.2, m, and n are as defined
under formula (I).
3. A process according to claim 2 wherein in formulas (I) and (II)
R.sup.1 represents COO--C.sub.1-C.sub.4-alkyl or two adjacent
R.sup.1 groups together represent a CO--N(benzyl)-CO group, R.sup.2
represents C.sub.1-C.sub.4-alkyl, n represents 1 or 2, and m
represents zero or 1.
4. A process according to claim 1 wherein the palladium-on-carbon
catalyst comprises from 1 to 10% by weight of palladium.
5. A process according to claim 1 wherein an amount of catalyst is
used such that from 0.5 to 30 mmol of palladium are present per
mole of the pyridine.
6. A process according to claim 1 wherein the aromatic
hydro-carbons are benzene, toluene, xylene, or other alkyl
aromatics.
7. A process according to claim 1 wherein the temperatures are in
the range from 20 to 200.degree. C.
8. A process according to claim 1 wherein the pressures are in the
range from 1 to 200 bar.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to an improved process for
preparing piperidines by hydrogenation of the ring of the
corresponding pyridines.
[0002] Piperidines are intermediates for the preparation of
pharmaceutically active compounds (see, for example, EP-A 603,887
and EP-A 5 350,733, particularly pages 2 and 17). Accordingly, they
have to be available in a form which is as pure as possible.
[0003] Activated piperidines are usually hydrogenated to the
corresponding piperidines using palladium catalysts in alcoholic
solvents, such as methanol, ethanol, isopropanol, or ethylene
glycol monomethyl ether (see Heterogenous Catalysis for the
Synthetics Chemist, New York 1996, Chapter 17, pages 421 to 424 and
EP-A 350,733, particularly pages 65 and 66). The reaction mixture
is generally worked up by removing catalyst and solvent. This gives
rise to piperidines that must be purified further, for example, by
crystallization, distillation, or chromatography. In this manner,
undesirable by-products contained in the piperidines are removed.
In addition to the expense associated with such a purification, the
loss of product that occurs during further purification is
disadvantageous, especially since the solvent is difficult to
recycle, due to the impurities contained therein.
[0004] Accordingly, there is still a need for a process for
preparing piperidines that does not require further purification of
the product isolated from the reaction mixture.
SUMMARY OF THE INVENTION
[0005] This invention, accordingly, provides a process for
preparing piperidines comprising catalytically hydrogenating
activated pyridines in the presence of a palladium catalyst and
aromatic hydrocarbon solvents, wherein the palladium catalyst is
palladium-on-carbon.
DETAILED DESCRIPTION OF THE INVENTION
[0006] Suitable activated pyridines for use in the process
according to the invention are, for example, those of formula (I)
1
[0007] in which
[0008] R.sup.1 represents COOR.sup.3, CONH.sub.2,
CO--NH--COR.sup.3, or COOH groups or two adjacent R.sup.1 groups
together represent a CO--NR.sup.4-CO group,
[0009] R.sup.2 represents linear or branched
C.sub.1-C.sub.20-alkyl,
[0010] R.sup.3 represents linear or branched C.sub.1-C.sub.6-alkyl,
phenyl, or benzyl,
[0011] R.sup.4 represents hydrogen, linear or branched
C.sub.1-C.sub.6-alkyl, phenyl, or benzyl,
[0012] n represents 1 or 2, and
[0013] m represents zero, 1, or 2.
[0014] If n represents 2, two identical or two different radicals
R.sup.1 may be present. Likewise, if m represents 2 , two identical
or different radicals R.sup.2 may be present.
[0015] Preferably, R.sup.1 represents COO--C.sub.1-C.sub.4-alkyl or
two adjacent R.sup.1 groups together represent a CO--N(benzyl)-CO
group, R.sup.2 represents C.sub.1-C.sub.4-alkyl, n represents 1 or
2, and m represents zero or 1.
[0016] If activated pyridines of the formula (I) are employed in
the process according to the invention, the corresponding
piperidines of formula (II) 2
[0017] in which R.sup.1, R.sup.2, m, and n are as defined under
formula (I), are obtained.
[0018] The palladium-on-carbon catalysts to be used according to
the invention can, for example, be catalysts that comprise from 1
to 10% by weight of palladium on any carbon. Preferably, the
catalysts comprise from 2 to 8% by weight of palladium. Suitable
catalysts are commercially available.
[0019] It is possible to use, for example, an amount of catalyst
such that from 0.5 to 30 mmol of palladium are present per mole of
activated pyridine. This amount is preferably from 2 to 15
mmol.
[0020] Suitable aromatic hydrocarbons are, for example, benzene,
toluene, xylenes, and other alkyl aromatics. Preference is given to
toluene. Based on 1 mole of activated pyridine, it is possible to
use, for example, from 50 to 5000 g of aromatic hydrocarbon (also
in the form of mixtures).
[0021] The catalytic hydrogenation according to the invention can
be carried out, for example, at temperatures in the range from 20
to 200.degree. C. Preference is given to temperatures in the range
from 50 to 150.degree. C., particularly those in the range from 60
to 100.degree. C. Suitable pressures are, for example, those in the
range from 1 to 200 bar. Preference is given to pressures in the
range from 3 to 150 bar, particularly those in the range from 5 to
60 bar.
[0022] The simultaneous use of temperatures and pressures close to
the upper limit should advantageously be avoided, since there is
otherwise a risk of the solvent being co-reduced.
[0023] After the catalytic hydrogenation has been carried out, the
reaction mixture that is present can be worked up, for example, by
removing the catalyst (for example, by filtration) and then
removing the aromatic hydrocarbon (for example, by distillation, if
appropriate under reduced pressure). Both the catalyst that has
been removed and the aromatic hydrocarbon that has been removed can
be recycled. If appropriate, fresh catalyst and fresh aromatic
hydrocarbon can be added to the recycled catalyst and the recycled
aromatic hydrocarbon, respectively.
[0024] Following removal of the catalyst and the aromatic
hydrocarbon, the piperidines that are prepared are generally
present in purities of more than 98%. Accordingly, further
purification is not necessary. As is shown in the Comparative
Examples, the customary procedure, which employs alcoholic
solvents, gives without further purification only piperidines of a
purity of about 94%. For the further use of piperidines as
intermediates for pharmaceutics, the purity that can be obtained
according to the invention is of decisive importance.
[0025] It is extremely surprising that, according to the present
invention, such an advantageous process has been found, since it
was not to be expected from the prior-art literature that high
yields and selectivities can be obtained in the heterogeneous
catalysis with palladium-on-carbon catalysts in nonpolar solvents.
Furthermore, it was to be expected that not only the pyridines
employed but also the aromatic hydrocarbons used as solvents should
be hydrogenated, resulting not only in contaminated products but
also, additionally, in a loss of solvent. However, the latter is
negligible.
EXAMPLES
[0026] In a 0.7 liter stirred autoclave fitted with stirrer,
temperature sensor and riser tube, 163.7 g of
pyridine-2,3-dicarboxylic acid N-benzylimide and 6.6 g of 5% by
weight palladium-on-carbon were suspended in 256.7 g of toluene.
The autoclave was flushed twice with nitrogen and then twice with
hydrogen. Under a hydrogen pressure of 5 bar, the autoclave was
then heated to 80.degree. C., and the hydrogen pressure was
increased gradually to 50 bar, so that the reaction temperature of
80.degree. C. could be maintained. After 50 bar had been reached,
stirring was continued at 80.degree. C. for 10 hours. The autoclave
was then cooled, the catalyst was removed from the reaction mixture
by filtration, and toluene was removed under reduced pressure using
a rotary evaporator. This gave 170 g of piperidine-2,3-dicarboxylic
acid N-benzylimide in a purity of 98.8% (GC area percent).
Example 2
[0027] Example 1 was repeated using 181.7 g of
pyridine-2,3-dicarboxylic acid N-benzylimide and hydrogenating at a
pressure of 10 bar. This gave 183.2 g of
piperidine-2,3-dicarboxylic acid N-benzylimide in a purity of 98.2%
(GC area percent).
Example 3
[0028] In a 1.3 liter stirred autoclave fitted with stirrer,
temperature sensor, and riser tube, 666 g of
pyridine-2,3-dicarboxylic acid N-benzylimide and 28.2 g of 5% by
weight palladium-on-carbon were suspended in 959 g of toluene. The
autoclave was then flushed, hydrogen was introduced, and the
autoclave was heated at a reaction temperature of 80.degree. C. as
described in Example 1. Work-up of the reaction mixture as
described in Example 1 gave 618 g of piperidine-2,3-dicarboxylic
acid N-benzylimide in a purity of 98.7% (GC area percent).
Example 4
[0029] In a 0.3 liter stirred autoclave fitted with stirrer and
temperature sensor, 19.52 g of dimethyl pyridine-2,3-dicarboxylate
and 2.25 g of 5% by weight palladium-on-carbon were initially
charged in 131 g of toluene. The autoclave was flushed twice with
nitrogen and then twice with hydrogen. The autoclave was then
heated to 80.degree. C. and, after this temperature had been
reached, a hydrogen pressure of 10 bar was applied and the mixture
was hydrogenated under these conditions for 4 hours. After the
reaction mixture had cooled, the catalyst was separated off by
filtration and toluene was removed under reduced pressure using a
rotary evaporator. This gave 19.13 g of dimethyl
cis-piperidine-2,3-dicar- boxylate in a purity of 98.7% (GC area
percent).
Comparative Example 1
(Solvent: isopropanol)
[0030] Example 2 was repeated except for using 261.7 g of
isopropanol instead of toluene. This gave 185.7 g of
piperidine-2,3-dicarboxylic acid N-benzylimide in a purity of 94%
(GC area percent).
Comparative Example 2
(Solvent: ethylene glycol monomethyl ether)
[0031] Example 1 was repeated except for using, instead of toluene,
the same amount of ethylene glycol monomethyl ether. This gave
171.1 g of piperidine-2,3-dicarboxylic acid N-benzylimide in a
purity of 94.8% (GC area percent).
[0032] Although the invention has been described in detail in the
foregoing for the purpose of illustration, it is to be understood
that such detail is solely for that purpose and that variations can
be made therein by those skilled in the art without departing from
the spirit and scope of the invention except as it may be limited
by the claims.
* * * * *